Diagnosis and treatment of ectopic endometriosis

Abstract

The present disclosure provides methods of detection and diagnosis of ectopic endometriosis. The disclosure further provides compositions, medicaments and methods for treating or preventing ectopic endometriosis.

1 . A method for detecting an ectopic endometrial mesenchymal stromal cell (E-MSC) or for detecting one or more ectopic E-MSCs in a test sample, the method comprising:
 probing a test cell or a test sample for the presence or expression of D 2  to determine a level of D 2 .   
     
     
         2 . The method of  claim 1 , wherein the test cell or test sample is further probed for:
 the presence or expression of endoglin (CD105) to determine a level of endoglin expression; and/or   the presence or expression of platelet derived growth factor receptor beta (PDGFRβ or CD140b) to determine a level of PDGFRβ expression.   
     
     
         3 . The method of  claim 1 or 2 , further comprising:
 (i) comparing the level of D 2  detected for the test cell or the test sample with a reference or control amount or level of D 2 , wherein the reference or control amount or level of D 2  is derived from a level of D 2  expression detected in a eutopic E-MSC or from a sample comprising eutopic E-MSCs; and/or   (ii) comparing the level of endoglin detected for the test cell or the test sample with a reference or control amount or level of endoglin, wherein the reference or control amount or level of endoglin is derived from a level of endoglin expression detected in a eutopic E-MSC or from a sample comprising eutopic E-MSCs; and/or   (iii) comparing the level of PDGFRβ detected for the test cell or the test sample with a reference or control amount or level of PDGFRβ, wherein the reference or control amount of PDGFRβ is derived from a level of PDGFRβ expression detected in a eutopic E-MSC or a sample comprising eutopic E-MSCs.   
     
     
         4 . The method of  claim 3 , wherein when the level of D 2  and/or endoglin and/or PDGFRβ detected for the test cell or the test sample is:
 (a) higher than the reference or control amount or level of D 2 , the test cell is determined to be an ectopic E-MSC or the test sample is determined to comprise one or more ectopic E-MSCs; and/or 
 (b) higher than the reference or control amount or level of endoglin, the test cell is determined to be an ectopic E-MSC or the test sample is determined to comprise one or more ectopic E-MSCs; and/or 
 (c) lower than the reference or control amount or level of PDGFRβ, the test cell is determined to be an ectopic E-MSC or the test sample is determined to comprise one or more ectopic E-MSCs. 
 
     
     
         5 . The method of any one of  claims 1 to 4 , further comprising one or more steps in which the test cell or the test sample is further or additionally probed for the presence or expression of one or more mesenchymal, haematopoietic, endometriotic, epithelial and/or endothelial markers. 
     
     
         6 . The method of any one of  claims 1 to 5 , further comprising:
 probing the test cell or the test sample for the presence or expression of one or more of the following:   (i) CD44 (a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration)   (ii) Ecto-5′-nucleotidase (CD73);   (iii) Sushi domain-containing protein 2 (SUSD2);   (iv) Integrin, beta 1 subunit (CD29); and   (v) CD90 (Thy-1);   
       wherein a test cell or test sample shown to express or contain an amount of one or more of the markers (i) to (v) is determined to be or to comprise an ectopic E-MSC. 
     
     
         7 . The method of any one of  claims 1 to 6 , further comprising:
 probing the test cell or test sample for the presence or expression of one or more of the following:   (a) melanoma cell adhesion molecule (CD146);   (b) CD34;   (c) RTP Type C (receptor tyrosine phosphatase, CD45);   (d) Epithelial cell adhesion molecule EpCAM and   (e) TEK receptor tyrosine kinase (TIE2);   
       wherein a test cell or test sample shown to express or contain a low amount or substantially no amount of any one or more of the markers (a)-(e) is determined to be or to comprise an ectopic E-MSC. 
     
     
         8 . A method of diagnosing ectopic endometriosis, the method comprising the steps of:
 detecting one or more ectopic endometrial mesenchymal stromal cells (E-MSC) in a test sample according to the method of any one of claims  1  to  7 ;   wherein when the test sample is determined to comprise one or more ectopic E-MSCs, the sample is identified as having been obtained from or provided by a subject who:   (i) is suffering from ectopic endometriosis;   (ii) is susceptible/predisposed to endometriosis; and/or   (iii) is convalescing from or is between occurrences of ectopic endometriosis.   
     
     
         9 . A method of diagnosing ectopic endometriosis according to  claim 8 , the method further comprising a step of allocating a treatment to a subject diagnosed as having or being susceptible to ectopic endometriosis, optionally wherein the method further comprises administering quinagolide to the subject. 
     
     
         10 . A kit for detecting ectopic endometrial mesenchymal stromal cells (E-MSCs), said kit comprising an anti-dopamine receptor 2 antibody. 
     
     
         11 . The kit of  claim 10 , wherein the kit further comprises an anti-endoglin antibody (anti-CD105 antibody) and/or anti-PDGFRβ antibody (anti-CD140 antibody). 
     
     
         12 . A kit according to any one of  claim 10 or 11 , further comprising one or more antibodies selected from the following:
 (i) an anti-CD44;   (ii) an anti-CD73;   (iii) an anti-CD146;   (iv) an anti-SUSD2;   (v) an anti-CD29;   (vi) an anti-CD90;   (vii) an anti-CD34;   (viii) an anti CD45;   (ix) an anti-EpPCAM; and   (x) an anti-TIEie2; and/or   further comprising one or more of:   (a) buffers;   (b) solutions;   (c) tools;   (d) receptacles; and   (e) instructions for use.   
     
     
         13 . A method of staging, assessing or monitoring ectopic endometriosis in a subject, or a method of determining whether or not ectopic endometriosis will re-occur in a subject, said method comprising providing a test sample and determining an amount of D 2  in said sample, wherein the amount of D 2  detected is correlated with or representative of, the stage or progression of ectopic endometriosis in the subject and/or the likelihood of ectopic endometriosis re-occurrence in the subject. 
     
     
         14 . The method of  claim 13 , wherein the sample is provided by:
 a healthy subject; or   a subject with ectopic endometriosis; or   a subject being treated for ectopic endometriosis; or   a subject convalescing or recovered from an episode of ectopic endometriosis; or   a subject in remission from ectopic endometriosis.   
     
     
         15 . The method of  claim 13 or 14 , wherein a relatively low amount of D 2  indicates that the sample has been provided by a healthy subject, a subject not suffering from ectopic endometriosis, a subject in remission from ectopic endometriosis and/or a subject responding to treatment for ectopic endometriosis. 
     
     
         16 . The method of any one of  claims 13 to 15 , wherein a relatively high amount of D 2  indicates that the sample has been provided by a subject with ectopic endometriosis, a worsening case of endometriosis and/or ectopic endometriosis which is not responding to treatment. 
     
     
         17 . The method of any one of  claims 13 to 16 , wherein repeat samples are provided by a subject to be tested for an amount of D 2 . 
     
     
         18 . The method of  claim 15 or 16 , wherein relatively high or relatively low amounts of D 2  are determined by comparing the amount of D 2  detected in the sample, with a control or reference amount of D 2 . 
     
     
         19 . The method of  claim 18 , wherein the reference or known amount of D 2  is indicative of a particular state or stage of ectopic endometriosis. 
     
     
         20 . A method of determining whether or not a subject needs prophylactic treatment and/or a hormone-based treatment for ectopic endometriosis, said method comprising providing a test sample from a subject to be considered for prophylactic treatment and/or a hormone-based treatment for ectopic endometriosis and determining an amount of D 2  in said sample, wherein the amount of D 2  detected is correlated with or representative of, the stage or progression of ectopic endometriosis in the subject and/or the likelihood of ectopic endometriosis re-occurrence in the subject. 
     
     
         21 . A D 2  agonist for use in treating or preventing ectopic endometriosis. 
     
     
         22 . A D 2  agonist for use in containing, controlling, restricting or inhibiting the growth, development or spread of ectopic endometriosis. 
     
     
         23 . Use of a D 2  agonist or a D 2  agonist for use, in inhibiting or preventing the invasive properties of ectopic E-MSCs. 
     
     
         24 . Use of a D 2  agonist or a D 2  agonist for use, in inhibiting, limiting or preventing the endothelial differentiation of an ectopic E-MSC. 
     
     
         25 . A method of inhibiting or preventing the invasive properties of ectopic E-MSCs, said method comprising contacting an ectopic E-MSC with a D 2  agonist. 
     
     
         26 . The method of  claim 25 , wherein the ectopic E-MSC is contacted with an invasion inhibiting or preventing amount of a D 2  agonist. 
     
     
         27 . A method of inhibiting, limiting or preventing the endothelial differentiation of an ectopic E-MSC, said method comprising contacting an ectopic E-MSC with a D 2  agonist. 
     
     
         28 . The method of  claim 27 , wherein the ectopic E-MSC is contacted with an endothelial differentiation inhibiting or limiting amount of a D 2  agonist. 
     
     
         29 . The method of any one of  claim 27 or 28 , wherein the method is conducted in an endothelial co-culture model of angiogenesis and said method comprises contacting an ectopic E-MSC with a D 2  agonist in an endothelial co-culture model of angiogenesis. 
     
     
         30 . The D 2  receptor agonist for use of any one of  claims 21 to 22 , the use of  claim 23 or 24 , or method of any one of  claims 25 to 28 , wherein the D 2  agonist is to be administered to a subject:
 (i) suffering from ectopic endometriosis; or   (ii) susceptible or predisposed to ectopic endometriosis; or   (iii) convalescing from or between occurrences of ectopic endometriosis.   
     
     
         31 . The D 2  receptor agonist for use of any one of  claims 21 to 22 and 30 , use of any one of  claims 23 to 24 and 30  or method of any one of  claims 25 to 30 , wherein the D 2  receptor agonist is quinagolide. 
     
     
         32 . Quinagolide for use in treating or preventing ectopic endometriosis. 
     
     
         33 . Quinagolide for use in containing, controlling, restricting or inhibiting the growth, development or spread of ectopic endometriosis. 
     
     
         34 . Use of quinagolide or quinagolide for use, in inhibiting or preventing the invasive properties of ectopic E-MSCs. 
     
     
         35 . Use of quinagolide or quinagolide for use, in inhibiting, limiting or preventing the endothelial differentiation of an ectopic E-MSCs. 
     
     
         36 . A method of inhibiting or preventing the invasive properties of ectopic E-MSC, said method comprising contacting an ectopic E-MSC with quinagolide. 
     
     
         37 . The method of  claim 36 , wherein the ectopic E-MSC is contacted with an invasion inhibiting or preventing amount of quinagolide. 
     
     
         38 . A method of inhibiting, limiting or preventing the endothelial differentiation of an ectopic E-MSCs, said method comprising contacting an ectopic E-MSC with quinagolide. 
     
     
         39 . The method of  claim 38 , wherein the ectopic E-MSC is contacted with an endothelial differentiation inhibiting or limiting amount of quinagolide 
     
     
         40 . The method of any one of  claim 38 or 39 , wherein the method is conducted in an endothelial co-culture model of angiogenesis and said method comprises contacting an ectopic E-MSC with quinagolide in an endothelial co-culture model of angiogenesis. 
     
     
         41 . Quinagolide for use of any one of  claims 32 to 35  or the method of any one of  claims 36 to 39 , wherein the quinagolide is to be administered to a subject:
 (i) suffering from ectopic endometriosis; 
 (ii) susceptible or predisposed to ectopic endometriosis; and/or 
 (iii) convalescing from or between occurrences of ectopic endometriosis. 
 
     
     
         42 . The use or D 2  agonist for use or method of any one of  claim 21 to 28 or 30  or the use or quinagolide for use or method of any one of  claim 32 to 39 or 41  wherein the D 2  agonist or quinagolide is formulated for intravaginal administration. 
     
     
         43 . The use or D 2  agonist for use or method of any one of  claim 21 to 28, 30 or 42  or the use, quinagolide for use or method of any one of  claims 32 to 39 or 41 to 42 , wherein the D 2  agonist or quinagolide is formulated together with one or more pharmaceutically acceptable excipients, diluents and/or carriers. 
     
     
         44 . The use or D 2  agonist for use or method of any one of  claim 21 to 28, 30, 42 or 43  or the use, quinagolide for use or method of any one of  claims 32 to 39 or 41 to 43 , wherein the D 2  agonist quinagolide is comprised within and/or loaded into a polymeric drug-device unit, optionally wherein the polymeric drug-device unit comprises a polyurethane block copolymer obtainable by reacting together:
 (a) a poly(alkylene oxide); 
 (b) a difunctional compound; 
 (c) a difunctional isocyanate; and 
 (d) optionally a block copolymer comprising poly(alkylene oxide) blocks. 
 
     
     
         45 . The use, quinagolide for use or method of any one of  claims 32 to 39 or 41 to 44 , wherein the quinagolide is selected from the group consisting of quinagolide, a pharmaceutically acceptable quinagolide salt, quinagolide hydrochloride, any active enantiomer, the quinagolide hydrochloride enantiomer with absolute configuration 3S,4aS,10aR, the quinagolide metabolite N-desethyl, the quinagolide metabolite N,N-didesethyl and pharmaceutically acceptable salts thereof. 
     
     
         46 . The method of any one of  claim 26 or 37 , wherein the invasion inhibiting amount is between about 1 and about 350 μg/per day of D 2  agonist or quinagolide. 
     
     
         47 . The method of any one of  claim 28 or 39 , wherein the endothelial differentiation inhibiting or limiting amount is between about 1 and about 350 μg/per day of D 2  agonist or quinagolide.